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Recent evidence indicates that CFTR is inhibited by a gluten\/gliadin-derived peptide (P31-43), causing an acquired state of CFTR inhibition within the gut that contributes to the pathogenesis of celiac disease (CD). Of note, CFTR inhibition does not only cause intra- and extracellular ion imbalances but also affects proteostasis by activating transglutaminase-2 (TGM2) and by disabling autophagy. These three phenomena (CFTR inhibition, TGM2 activation, and autophagy impairment) engage in multiple self-amplifying circuitries, thus forming an \u201cinfernal trio\u201d. The trio hinders enterocytes from returning to homeostasis and instead locks them in an irreversible pro-inflammatory state that ultimately facilitates T lymphocyte-mediated immune responses against another gluten\/gliadin-derived peptide (P57\u201368), which,upon deamidation by activated TGM2, becomes fully antigenic. Hence, the pathogenic protein gliadin exemplifies a food constituent the exceptional immunogenicity of which arises from a combination of antigenicity (conferred by deaminated P57\u201368) and adjuvanticity (conferred by P31-43). CF can be treated by agents targeting the \u201cinfernal trio\u201d including CFTR potentiators, TGM2 inhibitors, and autophagy enhancers. We speculate that such agents may also be used for CD therapy and indeed could constitute close-to-etiological treatments of this enteropathy.<\/jats:p>","DOI":"10.1038\/s41419-019-1392-9","type":"journal-article","created":{"date-parts":[[2019,2,8]],"date-time":"2019-02-08T13:46:35Z","timestamp":1549633595000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Defective proteostasis in celiac disease as a new therapeutic target"],"prefix":"10.1038","volume":"10","author":[{"given":"Luigi","family":"Maiuri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria R","family":"Villella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Piacentini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Raia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Kroemer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,2,8]]},"reference":[{"key":"1392_CR1","doi-asserted-by":"publisher","first-page":"647e55","DOI":"10.1038\/nri885","volume":"2","author":"LM Sollid","year":"2002","unstructured":"Sollid, L. 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